Antibody production, including class switching from IgM to IgG and IgA, is thought to be highly dependent upon engagement of CD40 on B cells by CD40 ligand (CD40L) on antigen-activated CD4+ T cells. Although inducing progressive CD4+ T cell depletion and CD40L down-regulation, HIV infection is associated with hypergammaglobulinemia and persistent systemic and mucosal production of IgG, IgA and IgE. A significant fraction of these class-switched antibodies specifically target gp120, an envelope glycoprotein that, similarly to canonical T cell-independent (TI) antigens, displays a repetitive antigenic structure. Antibodies to gp120potentially induce immune protection, as they prevent HIV cell entry by blocking the interaction of gp120 with the CD4 receptor on T cells and APCs. Unfortunately, HIV evades antibody-mediated neutralization by rapidly mutating gp120 and by inducing conformational masking of gp120's CD4-binding sites. Recent findings indicate that HIV-infected APCs produce more membrane-bound and soluble BLyS. Like its homologue APRIL, BLyS is an APC-derived CD40L-related molecule that stimulates TI antibody production, including class switching to IgG, IgA and IgE, by engaging TACI, BCMA and BAFF-R receptors on B cells. We contend here that, in HIV-infected patients, the immune system initiates TI antibody production against envelope glycoproteins as a mechanism to control viral infection in spite of the progressive loss of CD4+ T cells. Deregulation of this TI B cell-stimulating pathway, as induced by the continuous release of gp120,would lead to B cell hyperplasia, hypergammaglobulinemia, abnormally increased Ig class switching, autoantibody production and hyper-lgE syndrome. The goal of this project is to define the role of BLyS, APRIL and their receptors in the regulation of HIV-induced antibody responses and in the pathogenesis of HIV-associated B cell disorders. The studies outlined in this application might facilitate the development of new strategies aimed at enhancing the TI B cell production of neutralizing antibodies to gp120. They should also lead to the identification of new molecular targets for the treatment of HIV-associated B cell disorders. Aim 1. To analyze the mechanisms by which HIV up-regulates BLyS and APRIL in APCs. Aim 2. To analyze the role of BLyS and APRIL in the modulation of HIV-induced antibody production.